These computational approaches were complemented by <i>in vitro</i> HepG2 assays, luciferase reporter tests, iTRAQ proteomics, and an <i>in vivo</i> western diet/CCl<sub>4</sub> (WD/CCl<sub>4</sub>) HCC model using miR-29a transgenic mice to investigate a putative regulatory axis.<h4>Results</h4>MYBL2 robustly discriminated tumor from normal liver (AUC = 0.968), and high expression was associated with adverse features, including higher grade, microvascular invasion, HBV positivity, nonresponse to TACE, and worse survival. This evidence concerns the gene MYBL2 and hepatocellular carcinoma.